It has long been known to utilize coumarin analogs for various purposes such as to provide anti-thrombotic effects where needed. For example, one such analog known as Sodium Warfarin, which has been marketed under the tradename “Coumadin®” by the DuPont company, is considered the generally accepted standard in the field of coumarin analogs, although this drug has been marketed as a generic drug under other brand names such as Marevan; Prothromadin; Tintorane; Warfarin sodium; Warfilone; and Waran. Coumarin analogs such as sodium warfarin are disclosed, for example, in U.S. Pat. Nos. 2,427,578; 2,765,321; 5,591,403; and 6,512,005, incorporated herein by reference, and these compounds have been utilized primarily for the ability to provide localized anti-thrombotic effects as needed during therapeutic treatment.
However, such presently available coumarin analogs suffer from various drawbacks, including the fact that they may induce undesirable side effects. One example of undesirable effects relates to the extensive listing of unfavorable drug interactions for sodium warfarin, one in fact which is the most extensive among approved pharmaceuticals. Many of these unfavorable drug interactions arise because these analogs have been determined to bind serum albumin at a binding site common to many other drugs and compounds. This albumin binding site for many drugs is classically referred to as the Sudlow Site II. As a result, particularly in cases wherein a patient taking anti-coagulant drugs is taking a second medication at the same time, there is a great likelihood that the coumarin analog drug will be displaced from the serum albumin, resulting in the very dangerous situation where the analog will have an increased active concentration in the bloodstream which can result in serious metabolic consequences and other harmful conditions. Moreover, the useful life of the coumarin drug can be severely restricted and thus the patient may not be getting a sufficient supply of the blood-thinning drug which also may result in severe problems including blood clots, embolism, and even stroke.
Thus, although there have been numerous coumarin analogs synthesized and studied over the past several decades, none of these have been developed with a focus on the albumin protein binding characteristics of the various coumarin drugs that have been developed, and with the current heavy emphasis and expense in achieving product safety and efficacy, as well as regulatory approval, such an approach will be extremely helpful and cost effective in designing and selecting safe and effective coumarin alternatives earlier in the dug development process. It is thus needed in the field drug develop methods of obtaining coumarin alternatives using a focus which is structurally based on their protein binding properties, particularly the binding properties with serum albumin so as to best determine which analogs will bind to sites which have a far lesser likelihood of being displaced by other drugs or particular conditions in the bloodstream and which provide a stable and controlled reservoir of active drug in the blood stream.